Atypical, Non-V600 BRAF Mutations as a Potential Mechanism of Resistance to EGFR Inhibition in Metastatic Colorectal Cancer.
retrospective_cohort · Level III
Where this comes from
- Record sourced from PubMed, PMID 32914034.
- Also identified by DOI 10.1200/PO.19.00102 and PMC identifier 7446507.
- No licence information is recorded for this record.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
Abstract
Atypical, non-V600 BRAF (<i>aBRAF</i>) mutations represent a rare molecular subtype of metastatic colorectal cancer (mCRC). Preclinical data are used to categorize <i>aBRAF</i> mutations into class II (intermediate to high levels of kinase activity, <i>RAS</i> independent) and III (low kinase activity level, <i>RAS</i> dependent). The clinical impact of these mutations on anti-EGFR treatment efficacy is unknown. Data from 2,084 patients with mCRC at a single institution and from an external cohort of 5,257 circulating tumor DNA (ctDNA) samples were retrospectively analyzed. Overall survival (OS) was calculated using Kaplan-Meier and log-rank tests. Statistical tests were two-sided. BRAF mutations were harbored by 257 patients, including 36 with <i>aBRAF</i> mutations: 22 class III, 10 class II, four unclassified. For patients with <i>aBRAF</i> mCRC, median OS was 36.1 months, without a difference between classes, and median OS was 21.0 months for patients with <i>BRAF<sup>V600E</sup></i> mCRC. In contrast to right-sided predominance of tumors with <i>BRAF<sup>V600E</sup></i> mutation, 53% of patients with <i>aBRAF</i> mCRC had left-sided primary tumors. Concurrent <i>RAS</i> mutations were noted in 33% of patients with <i>aBRAF</i> mCRC, and 67% of patients had microsatellite stable disease. Among patients with <i>aBRAF RAS</i> wild-type mCRC who received anti-EGFR antibodies (monotherapy, n = 1; combination therapy, n = 10), no responses to anti-EGFR therapy were reported, and six patients (four with class III <i>aBRAF</i> mutations, one with class II, and one unclassified) achieved stable disease as best response. Median time receiving therapy was 4 months (range, 1 to 16). In the ctDNA cohort, there was an increased prevalence of <i>aBRAF</i> mutations and subclonal <i>aBRAF</i> mutations (<i>P</i> < .001 for both) among predicted anti-EGFR exposed compared with nonexposed patients. Efficacy of anti-EGFR therapy is limited in class II and III <i>aBRAF</i> mCRC. Detection of <i>aBRAF</i> mutations in ctDNA after EGFR inhibition may represent a novel mechanism of resistance.